Hydroarylation of (E)-5-(2-Arylethenyl)-2-methyl-2 H -tetrazoles under Superelectrophilic Activation

Article abstract of DOI:10.1055/s-0036-1588884

The reaction of 5-(2-arylethenyl)-2-methyl-2H-tetrazoles with arenes (benzene, xylenes, tert-butylbenzene, anisole, veratrole, 1,2-dichlorobenzene) under conditions of superelectrophilic activation under the action of Bronsted superacids (CF₃SO

Full text of DOI:10.1055/s-0036-1588884

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
A. D. Lisakova et al.
Paper
Synthesis
Hydroarylation of (E)-5-(2-Arylethenyl)-2-methyl-2H-tetrazoles
under Superelectrophilic Activation
Anna D. Lisakovaa
Brønsted (TfOH) or
Lewis (AlCl3, AlBr3) acid
Ar
Ar
Dmitry S. Ryabukhinb,c
Rostislav E. Trifonov*a,b
Vladimir A. Ostrovskiia
Irina A. Boyarskayab
N
N
N
N
Ar'H
Me
+
N
N
Me
N
17 examples
Ar'
up to 98%
N
Aleksander V. Vasilyev*b,c
a Saint Petersburg State Institute of Technology (Technical University),
Moskovsky pr., 26, Saint Petersburg, 190013, Russian Federation
b Institute of Chemistry, Saint Petersburg State University, Universitetskaya
nab., 7/9, Saint Petersburg, 199034, Russian Federation
c Department of Chemistry, Saint Petersburg State Forest Technical Univer-
sity, Institutsky per., 5, Saint Petersburg, 194021, Russian Federation
rost_trifonov@mail.ru
aleksvasil@mail.ru
a.vasilyev@spbu.ru
Received: 23.08.2016
Accepted after revision: 29.08.2016
Published online: 21.09.2016
showed that (Е)-2-methyl-5-(2-phenylethenyl)-2Н-tetra-
zole gave hydroarylation products of the C=C bond of the
styryl fragment in electrophilic aromatic substitution with
selected arenes under the action of the Brønsted superacid
CF3SO3H (TfOH) or strong Lewis acids AlX3 (AlCl3, AlBr3).
In general, the hydroarylation of 5-styryltetrazoles 1
gives rise to 5-(2,2-diarylethyl)tetrazoles 2 (Scheme 1).
Compounds 2 are close structural analogues of substances I
consisting of a chain of three carbon atoms and a functional
group (FG) on its one end and two aryl substituents on the
other one (Scheme 1). The structure I is general for many
bioactive substances. Compounds I, in which FG = NR2 ex-
hibit antihistaminic, choleretic, and anti-anginal activities,
and they are inhibitors of serotonin reuptake.11 Propanoic
acids and their derivatives possess properties of antagonists
of endothelinic receptors of A type (ETA), and are also char-
acterized by a high affinity and selectivity to these recep-
tors.12 In the case, when FG = SR, compounds I show antitu-
mor activity.13 One may expect that 5-(2,2-diaryleth-
yl)tetrazoles 2 containing the same structural fragments,
viz., two aryl groups, three carbon atoms and four nitrogen
atoms of the tetrazole ring, which can be considered as a
DOI: 10.1055/s-0036-1588884; Art ID: ss-2016-n0434-op
Abstract The reaction of 5-(2-arylethenyl)-2-methyl-2H-tetrazoles
with arenes (benzene, xylenes, tert-butylbenzene, anisole, veratrole,
1,2-dichlorobenzene) under conditions of superelectrophilic activation
under the action of Brønsted superacids (CF3SO3H, FSO3H) or strong
Lewis acids (AlCl3, AlBr3) leads regioselectively to the products of hy-
droarylation of the carbon–carbon double bond, viz., 5-(2,2-diarylethe-
nyl)-2-methyl-2H-tetazoles, in yields of up to 95%.
Key words tetrazoles, superelectrophilic activation, hydroarylation,
Brønsted superacid, Lewis superacid, Friedel–Crafts reaction
At the present time, the dynamic development of the
chemistry of tetrazole is observed.1 Tetrazole-containing
compounds and compositions based on them find applica-
tion as corrosion inhibitors,2 components of energetic ma-
terials,3 ionic liquids,4 etc. They are used in schemes for the
total synthesis of practically important compounds, the
preparation of which by other ways is associated with seri-
ous experimental difficulties or impossible at all.1,5–9 Vin-
yltetrazoles are also promising monomers for the synthesis
of appropriate tetrazole-containing polymers.1,4 Tetrazoles
containing substituents at endocyclic nitrogen and carbon
atoms exhibit antimicrobial,5 antidiabetic,6 and other types
of the biological activity.
Brønsted or
Lewis acid
Ar
Ar
N
N
N
N
+
Ar'H
N
R
N
R
N
Ar'
Ar
N
1
2
5-(2-Arylethenyl)-2-methyl-2H-tetrazoles
(5-styr-
Ar
FG
yltetrazoles) containing a carbon–carbon double bond in
the side chain can take part in chemical transformations
with the participation of this multiple bond. Reactions of
styryltetrazoles proceeding under superelectrophilic acti-
vation conditions with Brønsted or Lewis superacids are of
special interest. In preliminary brief communications,10 we
CO2R'
Ar'
Ar'
I
propanoic acids
and their derivatives
FG = NR2, SR, etc.
Scheme 1 Hydroarylation of 5-styryltetrazoles 1 leading to com-
pounds 2; general structure I for various biologically active compounds
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
A. D. Lisakova et al.
Paper
Synthesis
functional group, may also exhibit various types of biologi-
cal activity. In this regard, the synthesis of 5-(2,2-diaryleth-
yl)-substituted tetrazoles is an important task.
The goal of the present work was a systematic study of
the reactions of 5-(2-arylethenyl)-2-methyl-2H-tetrazoles
1а–е (Figure 1) with various arenes under the superelectro-
philic activation for the development of a general synthesis
of 5-(2,2-diarylethyl)-2-methyl-2Н-tetrazoles 2, as a result
of hydroarylation of the C=C bond of substrates 1.
cies refer to the class of highly reactive superelectrophiles.17
Analogously to related dications generated from conjugated
enone structures in superacids,11 dications B are reaction
intermediates under the superelectrophilic activation con-
ditions. The further interaction of dications B with arenes
gives hydroarylation products of the C=C bond 2.
1'
1'
Ar
Ar
2'
2'
N
N
N
N
H+
H+
N
Me
N
Me
N
HN
+
R
1a–e
Aa–e
1'
1'
Ar
Ar
2'
2'
+
N
N
N
N
N
1. ArH, – H+
2. H2O, – H+
N
Me
N
Me
N Me
N
Ar'
HN
N
N
+
1a R = H
2
Ba–e
Scheme 2 Protonation of 5-styryltetrazoles 1
1b R = Me
1c R = t-Bu
1d R = Cl
1e R = MeO
First, using quantum-chemical calculation by the DFT
method we studied cations A and B. The energies of HOMO
and LUMO, charges on atoms, contributions of the atomic
orbitals into LUMO, and indexes of the global electrophilici-
ty ω18 for the assessment of the reactivity of cations were
calculated. Table 1 contains electronic characteristics of the
species Аа, Ba,b,d,e. In comparison with cation Аа, di-
cations Ba,b,d,e have larger values of the electrophilicity in-
dex ω that reflects their high reactivity. Dications Bb and
Be, generated from compounds 1b and 1e, respectively,
with electron-donating substituents at the aromatic ring
have a smaller value of the index ω, compare to the phenyl-
substituted dication Ba (Table 1). Dications Ba,b,d,e are
characterized by a small positive charge on atom С2′, but on
this atom, a much larger part of LUMO of ~15–19% is locat-
ed (see Table 1). This indicates a pronounced orbital control
in the reactivity of such electrophiles.
Figure 1 (E)-5-(2-Arylethenyl)-2-methyl-2H-tetrazoles 1а–е used in
this study
It should be noted that the interaction of alkenes with
arenes under the action of Brønsted or Lewis superacids is
one of the major hydroarylation ways of the C=C bond.14
Apart from that, metal-catalyzed processes for alkene hy-
droarylation have a wide application (see reviews15a,b). The
most efficient catalysts for these purposes are complexes of
the following transition metals: Pt,15c Au,15d Ru,15e Rh,15f–h
Ni,15i Pd,15j or Pd/Ag.15k
The protonation of 5-styryltetrazoles 1a–e in Brønsted
acids (H2SO4, HClO4, etc.)16 first goes at the nitrogen atom
N4 of the tetrazole ring with the formation of cations Aa–e
(Scheme 2). Further, in stronger superacids, the protonation
of the atom С1′ of the C=C bond of the arylethenyl fragment
proceeds leading to dications Ba–e (Scheme 2). Such spe-
Table 1 Selected Calculated (DFT) Electronic Characteristics of Species Aa, Ba,b,d,e, Generated on Protonation of Tetrazoles 1a,b,d,e
Entry
Species, R
EHOMO (eV)
ELUMO (eV)
ωa (eV)
q(C2′)b (e)
k(C2′)LUMc (%)
1
2
3
4
5
Aa
–10.0
–15.0
–14.7
–14.5
–14.3
–6.5
–11.5
–11.0
–11.2
–10.4
9.7
25.0
22.3
25.0
19.6
–0.04
0.13
0.09
0.09
0.04
12.4
17.2
14.5
15.0
18.8
Ba, R = H
Bb, R = Me
Bd, R = Cl
Be, R = OMe
a Global electrophilicity index ω = (EHOMO + ELUMO)2/8(ELUMO – EHOMO).
b Natural charges.
c Contribution of atomic orbital into the molecular orbital.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
A. D. Lisakova et al.
Paper
Synthesis
We tried to register species B in superacids by means of
should be noted that reactions of tetrazoles 1а, 1e with
benzene in H2SO4 do not lead to the expected hydroaryla-
tion products (Table 2, entries 1, 24), that is for implement-
ing such transformations stronger acids should be used. Hy-
droarylation proceeds efficiently under the action of both
the Brønsted acids TfOH, FSO3H (entries 2, 6–23, 25, 28–
31), and strong Lewis acids AlCl3, AlBr3 (entries 3, 4, 18, 26,
27). Benzene, xylenes, tert-butylbenzene, anisole, and vera-
trole, and even a low-nucleophilic arene, such as 1,2-di-
chlorobenzene, may be involved in this reaction (Table 2).
The tetrazole 1а in reactions with mesitylene and durene
did not give appropriate hydroarylation products (entries 8,
9), apparently, due to steric hindrance from the side of the
methyl groups of these arenes. Oligomeric products were
obtained in these cases.
1
NMR. However, according to the data of H and 13C NMR,
upon dissolving in TfOH at room temperature or in FSO3H at
–80 °C, tetrazoles 1а–е formed oligomeric substances. This
indicates an extreme instability and high reactivity of dicat-
ions B. Then, we carried out reactions of tetrazoles 1a and
1e in TfOH at room temperature and isolated products of
cationic oligomerization. According to the data of MALDI
mass spectrometry, the oligomers consist of no more than 9
subunits of the initial tetrazoles 1a and 1e (see the Support-
ing Information).
Then, hydroarylation reactions of the C=C bond of styr-
yltetrazoles 1а–е by arenes under the superelectrophilic
activation conditions leading to 5-(2,2-diarylethyl)-2-
methyl-2H-tetrazoles) 2a–s were carried out (Table 2). It
Table 2 Hydroarylation of 5-Styryltetrazoles 1a–e with Arenes under Superelectrophilic Activation with Brønsted (TfOH, FSO3H) or Lewis (AlCl3, AlBr3)
Acids Leading to Compounds 2a–s
R1
R1
N
N
N
acid
+
N
Me
N
Me
N
N
N
R2
1a–e
2a–s
R2
Entry
Starting materials
Tetrazole
Reaction conditionsa Reaction product
R2 in arene
H
2
R1
R2
Yield (%)
1
2
1a, R1 = H
E
unreacted initial 1a
A
B
C
G
A
A
A
A
A
2a
H
H
70
95
90
98
73
80
3
4
5
6
1,3-Мe2
1,4-Мe2
1,3,5-Мe3
2b
H
H
2,4-Мe2
2,5-Мe2
7
2c
8
oligomers
9
1,2,4,5-Мe4
t-Bu
oligomers
10
2a
2d
2e
2f
H
H
46
14
27
30
96
62
24
66
10
59
29
67
H
4-t-Bu
3,4-Cl2
2,3-Cl2
3,4-Cl2
4-МeO
2-МeO
3,4-(МeO)2
2,3-(МeO)2
H
11
1,2-Cl2
Ab
H
H
12
13
G
2e
2g
2h
2i
H
МeO
Ac
H
H
14
15
16
1,2-(МeO)2
Ad
A
H
2j
H
1b, R1 = Me
H
2a
2k
2k
H
Мe
Мe
H
D
H
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
A. D. Lisakova et al.
Paper
Synthesis
Table 2 (continued)
Entry
Starting materials
Reaction conditionsa Reaction product
Tetrazole
R2 in arene
H
2
R1
R2
Yield (%)
17
18
19
1c, R1 = t-Bu
A
2a
H
H
46
58
63
21
15
8
B
2a
H
H
1,3-Мe2
МeO
Ae
2b
H
2,4-Мe2
3,5-Мe2
4-МeO
4-МeO
H
2l
H
20
D
2m
2g
t-Bu
H
21
22
23
1d, R1 = Cl
МeO
A
2n
Cl
Cl
Cl
Cl
48
86
72
11
1,2-Cl2
МeO
A
2o
3,4-Cl2
4-МeO
2-МeO
Af
2p
2q
24
25
26
27
1e, R1 = OMe
H
E
oligomers
2a
A
B
C
H
H
51
44
74
24
73
85
21
35
2g
OМe
H
H
2a
H
2g
OМe
OМe
OМe
OМe
OМe
H
28
29
30
31
F
2g
H
D
A
A
2g
H
1,3-Мe2
МeO
2r
2,4-Мe2
4-МeO
2s
a A: ТfOH, r.t., 3 h; B: AlCl3, СH2Cl2, r.t., 3 h; C: AlBr3, r.t., 3 h; D: FSO3H, CH2Cl2, –80 °C, 4 h; E: H2SO4 96%, r.t., 3 h; F: ТfOH, CH2Cl2, 0 °C, 4 h; G: ТfOH, 120 °C, 5
min, microwave irradiation.
b Ratio of isomers 2e/2f is 1:1.
c Ratio of isomers 2g/2h is 2.6:1.
d Ratio of isomers 2i/2j is 6.6:1.
e Ratio of isomers 2b/2l is 3:1.
f Ratio of isomers 2p/2q is 6.5:1.
Tetrazoles 1b, 1e having electron-donating methyl and
methoxyl groups in the aromatic ring in the reaction with
benzene under the action of TfOH or AlBr3 at room tem-
perature, in addition to the target substances 2k and 2g,
also give 2a (entries 15, 25, 27). The latter is formed as the
product of an exchange of aryl groups for the phenyl. Simi-
lar exchanges were observed by us previously in hydroary-
lation reactions of amides of cinnamic acids.14p We man-
aged to completely suppress the exchange by decreasing the
reaction temperature in CF3SO3H to 0 °C (entry 28) or in
FSO3H to –80 °C (entries 16, 29).
In the reaction of the tert-butyl-substituted tetrazole 1c
with arenes in TfOH (entries 17, 19) and AlCl3 (entry 18) or
when tetrazole 1a interacts with tert-butylbenzene (entry
10) at room temperature, the formation of products 2a,b,l,
not containing the tert-butyl substituent was observed. In
this case, ipso-substitution of the tert-butyl group by a pro-
ton under superacidic conditions takes place. We were able
to suppress this process partially at a low temperature of
–80 °C in FSO3H (entry 20).
Some individual aromatic substrates gave regioisomeric
reaction products. Thus, in some cases, reactions with
anisole (2g + 2h, entry 13), veratrole (2i + 2j, entry 14),
meta-xylene (2b + 2l, entry 19), and 1,2-dichlorobenzene
(2e + 2f, entry 11) gave substitution products at various po-
sitions of the aromatic ring of these arenes. This indicates
the high reactivity of intermediate dications B (see Scheme
2).
As a whole, this reaction is an efficient hydroarylation
method of the C=C bond of 5-styryltetrazoles 1 and in the
majority of cases leads to the target products in good yields
of 60–95%. Transformations of substances 1 in superacids
proceed regioselectively only at the C=C bond and does not
affect the tetrazole cycle.
Despite the advantages of the method proposed by us, it
is obvious that an important task is the minimization of the
reaction time. To intensify chemical processes microwave
(MW) activation is widely used.19 We checked the possibili-
ty of conducting the studied hydroarylation reaction in
TfOH under the conditions of microwave irradiation. Truly,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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A. D. Lisakova et al.
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Synthesis
microwave irradiation allows a sharp reduction in the reac-
tion time to 5 minutes at 120 °C for the interaction of tetra-
zole 1а with benzene and 1,2-dichlorobenzene to form sub-
stances 2a (yield of 98%) and 2e (yield of 96%) (entries 5,
12). Under thermal conditions, these reactions proceeded
in 3 hours at room temperature (entries 2, 11).
In summary, we developed an efficient method of the
synthesis of 5-(2,2-diarylethyl)-2-methyl-2H-tetrazoles
based on reactions of 5-(2-arylethenyl)-2-methyl-2H-tetra-
zoles with arenes under the superelectrophilic activation
with Brønsted or Lewis acids.
5-(2,2-Diarylethyl)-2-methyl-2H-tetrazoles 2 from Tetrazoles 1
and Benzene under the Action of AlCl3 or AlBr3; General Procedure
(Table 2)
Tetrazole 1 (0.27 mmol) was added to a solution of AlX3 (X = Cl, Br)
(1.34 mmol) in benzene (4 mL) at r.t. The mixture was stirred at r.t. for
3 or 4 h (as indicated in Table 2). Then the mixture was poured into
water (20 mL), sat. aq NaHCO3 solution was added to pH 8–9, and re-
action product was extracted with CHCl3 (3 × 30 mL). The combined
extracts were dried (Na2SO4), the solvent was distilled off under re-
duced pressure, and the residue was subjected to chromatographic
separation (silica gel, petroleum ether–Et2O).
Yields of compounds 2a–r are given in Table 2.
Properties of 2-methyl-5-(2,2-diphenylethyl)-2H-tetrazole (2a), 2-
methyl-5-[2-(2,4-dimethylphenyl)-2-phenylethyl]-2H-tetrazole (2b),
2-methyl-5-[2-(2,5-dimethylphenyl)-2-phenylethyl]-2H-tetrazole (2c),
5-[2-(4-methoxyphenyl)-2-phenylethyl]-2-methyl-2H-tetrazole (2g),
5-[2-(2-methoxyphenyl)-2-phenylethyl]-2-methyl-2H-tetrazole (2h),
5-[2-(3,4-dimethoxyphenyl)-2-phenylethyl]-2-methyl-2H-tetrazole
(2i), 5-[2-(2,3-dimethoxyphenyl)-2-phenylethyl]-2-methyl-2H-tetra-
zole (2j) were previously reported.10
The NMR spectra of solutions of compounds in CDCl3 were recorded
on a Bruker AM-500 spectrometer at 25 °C (at 500 and 125 MHz for
1H and 13C NMR spectra, respectively). The residual proton solvent
peak CDCl3 (δ = 7.26) for 1H NMR spectra, and the carbon signal of
CDCl3 (δ = 77.0) for 13C NMR spectra were used as references. IR spec-
tra of compounds in KBr were taken with Shimadzu IR Affinity-1
spectrometer in region 400–4000 cm–1 with resolution 4 cm–1, Happ-
Genzel apodization, 20 scans. HRMS was carried out at an instrument
Bruker MicroTOF (ESI). GC-MS: data were obtained at a machine
G2570A GC/MSD Agilent Technologies 6850c with a column HP-5MS
(3 m × 0.25 mm), a thickness of the stationary phase 0.25 μm. Micro-
wave reactions were carried out at a machine DISCOVER SP. The pre-
parative reactions were monitored by TLC on silica gel plates (Silufol
UV-254) using UV light for detection. Column chromatography was
performed on silica gel Chemapol 40/100 (0.04–0.10 mm) eluting
with petroleum ether–Et2O mixtures.
5-[2-(4-tert-Butylphenyl)-2-phenylethyl]-2-methyl-2H-tetrazole
(2d)
Obtained as an oily yellow mixture with compound 2a; yield: 23 mg
(14%).
IR (KBr) (for mixture of isomers): 2925, 2855, 1600, 1495, 1449, 1388,
1278, 1200, 1077, 1035, 778, 705, 611 cm–1
.
1Н NMR (500 МHz, CDCl3, from the spectrum of the mixture): δ = 1.30
(s, 9 H, 3 CH3), 3.60 (d, J = 8.2 Hz, 2 H, CH2), 4.20 (s, 3 H, CH3), 4.64 (t,
J = 8.2 Hz, 1 H, CH), 7.17–7.31 (m, 9 Нarom).
13С NMR (125 МHz, CDCl3, from the spectrum of the mixture): δ =
31.6, 34.8, 39.1, 49.2, 126.2, 126.5, 127.8, 128.4, 128.6, 141.5, 143.3,
165.1.
All computations has been carried out at the DFT/HF hybrid level of
theory using Becke’s three-parameter hybrid exchange functional in
combination with the gradient-corrected correlation functional of
Lee, Yang, and Parr (B3LYP) by using GAUSSIAN 2003 program pack-
ages.20 The geometries optimization were performed using the 6-
311+G(2d,2p) basis set. The Hessian matrix was calculated analytical-
ly for the optimized structures in order to prove the location of cor-
rect minima (no imaginary frequencies) and to estimate the thermo-
dynamic parameters.
HRMS: m/z [M + H]+ calcd for C20H25N4: 321.2074; found: 321.2071.
5-[2-(3,4-Dichlorophenyl)-2-phenylethyl]-2-methyl-2H-tetrazole
(2e)
White solid; yield: 80 mg (96%); mp 120–121 °C.
Starting 5-(2-arylethenyl)-2-methyl-2H-tetrazoles 1a–e were synthe-
IR (KBr): 2922, 1722, 1592, 1562, 1493, 1470, 1445, 1396, 1309, 1155,
sized and characterized by us previously.21
1030, 822, 702, 565 cm–1
.
1Н NMR (500 МHz, CDCl3): δ = 3.58 (d, J = 8.0 Hz, 2 H, CH2), 4.23 (s, 3
H, CH3), 4.65 (t, J = 8.0 Hz, 1 H, CH), 7.10–7.33 (m, 8 Нarom).
13С NMR (125 МHz, CDCl3): δ = 31.3, 39.2, 48.3, 126.6, 127.2, 127.7,
5-(2,2-Diarylethyl)-2-methyl-2H-tetrazoles 2 from Tetrazoles 1
and Arenes in TfOH; General Procedure (Table 2)
Tetrazole 1 (0.25 mmol) was added to a mixture of arene (0.3 mmol)
and TfOH (1 mL) at r.t. (or other temperature as indicated in Table 2).
The mixture was stirred at r.t. for 3 h (or other times and tempera-
tures as indicated in Table 2). Then the mixture was poured into wa-
ter (20 mL), sat. aq NaHCO3 solution was added to pH 8–9, and reac-
tion product was extracted with CHCl3 (3 × 30 mL). The combined ex-
tracts were dried (Na2SO4), the solvent was distilled off under
reduced pressure, and the residue was subjected to chromatographic
separation (silica gel, gradient petroleum ether–Et2O).
127.8, 128.2, 128.5, 129.9, 130.4, 140.4, 143.4, 165.1.
HRMS: m/z [M
+
H]+ calcd for C16H15N4Cl2: 333.0668; found:
333.0670.
5-[2-(2,3-Dichlorophenyl)-2-phenylethyl]-2-methyl-2H-tetrazole
(2f)
Obtained as an oily yellow mixture with compound 2e; yield: 27 mg
(30%).
In the same manner, reactions were carried out in TfOH (1 mL) at 0 °C,
or FSO3H (1 mL) at –80 °C (see Table 2), CH2Cl2 (1 mL) was added for
better solubility of benzene.
IR (KBr) (for mixture of isomers): 2924, 2953, 1676, 1602, 1499, 1468,
1255, 1171, 1028, 742, 699 cm–1
.
1Н NMR (500 МHz, CDCl3, from the spectrum of the mixture): δ =
3.50–3.52 (m, 2 H, CH2), 4.16 (s, 3 H, CH3), 4.52–4.59 (m, 1 H, CH),
7.05–7.33 (m, 8 Нarom).
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A. D. Lisakova et al.
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Synthesis
13С NMR (125 МHz, CDCl3, from the spectrum of the mixture): δ =
31.6, 39.1, 49.2, 126.5, 127.0, 127.6, 127.8, 128.5, 128.8, 130.5, 132.4,
142.2, 143.3, 164.5.
GC-MS: m/z (%) = 298 [M]+ (16), 201 (100), 165 (55).
HRMS: m/z [M + H]+ calcd for C16H16СlN4: 299.1058; found: 299.1058.
HRMS: m/z [M
333.0670.
+
H]+ calcd for C16H15N4Cl2: 333.0668; found:
5-[2-(4-Chlorophenyl)-2-(3,4-dichlorophenyl)ethyl]-2-methyl-2H-
tetrazole (2o)
Yellow oil; yield: 44 mg (86%).
2-Methyl-5-[2-(4-methylphenyl)-2-phenylethyl]-2H-tetrazole (2k)
Colorless oil; yield: 30 mg (67%).
IR (KBr): 2961, 2862, 1600, 1464, 1382, 1275, 1124, 1073, 1040, 743
cm–1
.
IR (KBr): 2960, 2861, 1602, 1494, 1463, 1382, 1276, 1123, 1073, 1037,
1Н NMR (500 МHz, CDCl3): δ = 3.55 (d, J = 8.2 Hz, 2 H, CH2), 4.23 (s, 3
H, CH3), 4.63 (t, J = 8.2 Hz, 1 H, CH), 7.08 (d, J = 8.4 Hz, 1 Нarom), 7.16 (d,
J = 8.4 Hz, 2 Нarom), 7.25 (d, J = 8.4 Hz, 2 Нarom), 7.30 (s, 1 Нarom), 7.33 (d,
J = 8.3 Hz, 1 Нarom).
820, 744, 703 cm–1
.
1Н NMR (500 МHz, CDCl3): δ = 2.29 (s, 3 H, CH3), 3.63 (d, J = 8.2 Hz, 2
H, CH2), 4.21 (s, 3 H, CH3), 4.69 (t, J = 8.2 Hz, 1 H, CH), 6.98–6.99 (m, 1
Н
Н
arom), 7.06–7.08 (m, 2 Нarom), 7.14–7.16 (m, 2 Нarom), 7.17–7.18 (m, 2
arom), 7.27 (s, 2 Нarom).
13С NMR (125 МHz, CDCl3): δ = 31.3, 39.3, 48.0, 127.1, 128.9, 129.0,
129.8, 130.6, 130.9, 132.7, 132.9, 140.6, 143.1, 164.3.
GC-MS: m/z (%) = 366 [M]+ (14), 269 (100), 233 (12), 199 (65), 163
(14).
13С NMR (125 МHz, CDCl3): δ = 20.9, 31.6, 39.2, 49.3, 126.4, 127.8,
128.4, 129.0, 130.8, 133.0, 135.8, 140.0, 165.3.
GC-MS: m/z (%) = 278 [M]+ (20), 181 (100), 165 (30), 115 (5).
HRMS: m/z [M + H]+ calcd for C17H19N4: 279.1604; found: 279.1593.
HRMS: m/z [M
+
H]+ calcd for C16H14Сl3N4: 367.0279; found:
367.0274.
2-Methyl-5-[2-(3,5-dimethylphenyl)-2-phenylethyl]-2H-tetrazole
5-[2-(4-Chlorophenyl)-2-(4-methoxyphenyl)ethyl]-2-methyl-2H-
(2l)
tetrazole (2p)
Obtained as an yellow oily mixture with compound 2b; yield: 20 mg
Obtained as an yellow oily mixture with compound 2q; yield: 59 mg
(21%).
(72%).
IR (KBr) (for mixture of isomers): 2920, 1602, 1495, 1450, 1387, 1193,
IR (KBr) (for mixture of isomers): 2927, 2837, 1610, 1512, 1492, 1408,
1033, 850, 705 cm–1
.
1250, 1180, 1092, 1033, 825, 785 cm–1
.
1Н NMR (400 МHz, CDCl3, from the spectrum of the mixture): δ = 2.26
(s, 6 H, 2 CH3), 3.57 (d, J = 8.2 Hz, 2 H, CH2), 4.20 (s, 3 H, CH3), 4.55 (t,
J = 8.2 Hz, 1 H, CH), 6.90 (s, 8 Нarom).
1Н NMR (500 МHz, CDCl3, from the spectrum of the mixture): δ = 3.55
(d, J = 8.2 Hz, 2 H, CH2), 3.75 (s, 3 H, ОCH3), 4.20 (s, 3 H, CH3), 4.61 (t,
J = 8.2 Hz, 1 H, CH), 7.14–7.22 (m, 8 Нarom).
13С NMR (100 МHz, CDCl3, from the spectrum of the mixture): δ =
21.3, 31.6, 39.1, 49.4, 125.6, 126.4, 126.5, 127.8, 128.1, 128.2, 128.4,
137.8, 143.3, 165.3.
13С NMR (125 МHz, CDCl3, from the spectrum of the mixture): δ =
31.7, 39.2, 48.1, 55.2, 114.0, 128.2, 128.6, 129.1, 132.1, 135.0, 142.1,
158.3, 165.0.
HRMS: m/z [M + H]+ calcd for C18H21N4: 293.1761; found: 293.1783.
GC-MS: m/z (%) = 328 [M]+ (5), 231 (100), 196 (5), 181 (5), 165 (5),
153 (12).
+
H]+ calcd for C17H18СlN4O: 329.1164; found:
5-[2-(4-tert-Butylphenyl)-2-(4-methoxyphenyl)ethyl]-2-methyl-
2H-tetrazole (2m)
HRMS: m/z [M
329.1169.
Obtained as an yellow oily mixture with compound 2g; yield: 26 mg
(15%).
5-[2-(4-Chlorophenyl)-2-(2-methoxyphenyl)ethyl]-2-methyl-2H-
tetrazole (2q)
IR (KBr) (for mixture of isomers): 2961, 1610, 1512, 1464, 1303, 1249,
1180, 1113, 1033, 837, 701 cm–1
.
Obtained as an yellow oily mixture with compound 2p; yield: 9 mg
(11%).
1Н NMR (500 МHz, CDCl3, from the spectrum of the mixture): δ = 1.27
(s, 9 H, 3 CH3), 3.58–3.60 (m, 2 H, CH2), 3.75 (s, 3 H, OCH3), 4.20 (s, 3 H,
CH3), 4.64 (t, J = 8.2 Hz, 1 H, CH), 7.16–7.19 (m, 4 Нarom), 7.25–7.26 (m,
4 Нarom).
13С NMR (125 МHz, CDCl3, from the spectrum of the mixture): δ =
31.3, 34.3, 39.2, 48.3, 55.1, 113.8, 125.4, 126.4, 127.2, 128.7, 135.4,
140.8, 149.1, 165.4.
IR (KBr) (for mixture of isomers): 2927, 2837, 1610, 1512, 1492, 1408,
1250, 1180, 1092, 1033, 825, 785 cm–1
.
1Н NMR (500 МHz, CDCl3): δ = 3.68 (d, J = 8.2 Hz, 2 H, CH2), 3.80 (s, 3
H, ОCH3), 4.20 (s, 3 H, CH3), 4.94 (t, J = 8.2 Hz, 1 H, CH), 6.79–6.81 (m,
8 Нarom).
13С NMR (125 МHz, CDCl3): δ = 31.7, 39.2, 48.1, 55.2, 114.0, 128.2,
128.6, 129.1, 132.1, 135.0, 142.1, 158.3, 165.0.
HRMS: m/z [M + H]+ calcd for C21H27N4O: 351.2179; found: 351.2180.
GC-MS: m/z (%) = 328 [M]+ (13), 297 (28), 231 (81), 165 (40), 152 (11),
125 (100).
5-[2-(4-Chlorophenyl)-2-phenylethyl]-2-methyl-2H-tetrazole (2n)
+
H]+ calcd for C17H18СlN4O: 329.1164; found:
Colorless solid; yield: 36 mg (48%); mp 91–92 °C.
IR (KBr): 2960, 1602, 1464, 1382, 1286, 1125, 1074, 744 cm–1
HRMS: m/z [M
329.1169.
.
1Н NMR (500 МHz, CDCl3): δ = 3.59 (d, J = 8.2 Hz, 2 H, CH2), 4.21 (s, 3
H, CH3), 4.67 (t, J = 8.2 Hz, 1 H, CH), 7.18–7.25 (m, 8 Нarom), 7.27–7.29
(m, 1 Нarom).
5-[2-(4-Methoxyphenyl)-2-(2,4-dimethylphenyl)ethyl]-2-methyl-
2H-tetrazole (2r)
Colorless oil; yield: 17 mg (21%).
13С NMR (125 МHz, CDCl3): δ = 31.5, 39.2, 48.9, 126.7, 127.7, 128.6,
128.7, 129.2, 132.3, 141.7, 142.9, 164.9.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
A. D. Lisakova et al.
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Synthesis
IR (KBr): 2936, 2838, 1606, 1512, 1452, 1352, 1292, 1249, 1177, 1030,
834, 768 cm–1
1Н NMR (500 МHz, CDCl3): δ = 2.25 (s, 6 H, 2 CH3), 3.56 (d, J = 8.0 Hz, 2
H, CH2), 3.75 (s, 3 H, OCH3), 4.21 (s, 3 H, CH3), 4.56 (t, J = 8.0 Hz, 1 H,
CH), 6.78–6.80 (m, 3 Нarom), 6.88–6.91 (m, 2 Нarom), 7.17 (d, J = 8.0 Hz,
2 Нarom).
13С NMR (125 МHz, CDCl3): δ = 21.3, 31.8, 39.2, 48.7, 55.2, 113.8,
125.5, 125.9, 128.0, 128.1, 128.8, 135.6, 137.9, 143.7, 158.0, 165.5.
HRMS: m/z [M + H]+ calcd for C19H23N4O: 323.1866; found: 323.1877.
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Thieme Verlag: Stuttgart, 1987. (b) Giringauz, A. Medicinal
Chemistry; Wiley: New York, 1997. (c) Simons, F. E. R.; Fritch, E.
M.; Simons, K. J. Allergy Clin. Immunol. 1982, 70, 458. (d) Piper,
H. M.; Hutler, J. F.; Spieckerman, P. G. Arzneim. Forsch. 1985, 35,
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5-[2,2-Bis(4-methoxyphenyl)ethyl]-2-methyl-2H-tetrazole (2s)
White solid; yield: 28 mg (35%); mp 94–95 °C.
IR (KBr): 2937, 2836, 1607, 1582, 1512, 1464, 1302, 1250, 1179, 1115,
1028, 835, 806, 767 cm–1
.
1Н NMR (500 МHz, CDCl3): δ = 3.56 (d, J = 8.2 Hz, 2 H, CH2), 3.74 (s, 6
H, OCH3), 4.20 (s, 3 H, CH3), 4.59 (t, J = 8.2 Hz, 1 H, CH), 6.79 (d, J = 8.7
Hz, 4 Нarom), 7.16 (d, J = 8.7 Hz, 4 Нarom).
13С NMR (125 МHz, CDCl3): δ = 32.0, 39.1, 48.0, 55.1, 113.8, 128.6,
135.9, 158.0, 165.3.
GC-MS: m/z (%) = 324 [M]+ (10), 227 (100), 196 (5), 181 (6), 165 (8).
HRMS: m/z [M + H]+ calcd for C18H21N4O2: 325.1659; found: 325.1654.
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Acknowledgement
This work was supported by the Russian Foundation for Basic Re-
search (grant no. 15-03-02936-a) and St. Petersburg State University
(grant. no. 12.38.428.2015).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588884.
S
u
p
p
ortioInfgrmoaitn
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u
p
p
ortiInfogrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H